Pregnancy specific glycoproteins (PSGs) are a family of secreted proteins produced by the placenta. These proteins belong to the immunoglobulin gene super family and are essential for a successful pregnancy. Expression of PSGs has been observed in many species including humans and mice. Our long-range goal is to define the roles and mechanisms of action of pregnancy specific glycoproteins in normal and abnormal pregnancy. The objective of this application is to characterize the initial interaction of PSGs with receptor-bearing target cells to clone their receptor, to clone their receptor, and to evaluate their ability to regulate the production of cytokines and other mediators of inflammation. The central hypothesis of the application is that PSGs bind to a specific cellular receptor on target cells and that this interaction contributes to the regulation of immune and inflammatory mediators which are essential for a normal pregnancy outcome. The rationale behind the proposed research is that PSGs are involved, through binding to a specific cellular receptor on mononuclear phagocytes in modulating mediators of the immune response, such as IL-10, thereby preventing the feto-placental damage that could ensue from local inflammation. The future development of therapeutic interventions, aimed at manipulation of immunomodu-latory effects of PSGs during pregnancy, will depend on careful definition of specific PSG functions. To accomplish the objectives of this application, we will pursue two specific aims: (1) Clone and characterize the cDNA encoding the cellular receptor for murine PSGs on murine macrophages; (2) Characterize the roles of murine PSG2, PSG3, and PSG4 and human PSG6 as immunomodulators in vitro. We expect that the results obtained will aid in the definition of the roles of this glycoprotein family in maintaining normal pregnancy and that this knowledge will result in the development of new therapeutic strategies related to the management of complicated pregnancies.